The knowledge that cancer cells rely on increased glycolysis rather than oxidative phosphorylation for survival is known as the “Warburg hypothesis” (Warburg (1956) Science 123:309-314). This concept constitutes the basis for using glycolysis and its associated enzymes as unique targets for the development of new anticancer therapeutic agents (Shaw (2006) Curr. Opin. Cell Biol. 18:598-608; Gatenby and Gillies (2007) Biochem. Cell Biol. 39:1358-1366). One such agent is 3-bromopyruvate (3-BrPA), a synthetic brominated derivative of pyruvic acid that acts as an irreversible glycolytic inhibitor (Ko et al. (2001) Cancer Lett. 173:83-91; Geschwind et al. (2002) Cancer Res. 62:3909-3913). It disrupts energy metabolism by targeting the glycolytic enzyme, glyceradehyde-3 phosphate dehydrogenase (GAPDH) (Ganapathy-Kanniappan et al. (2009) Anticancer Res. 29:4909-4918). Further, the anticancer effects of 3-BrPA have been consistent and reproducible against multiple tumor models both in vitro and in vivo. A wide variety of tumors have been demonstrated to be sensitive to 3-BrPA treatment, including, for example, liver cancer (Geschwind et al. (2002) Cancer Res. 62:3909-30913; Vali et al. (2007) J. Vasc. Interv. Radiol. 18:95-101; and Ganapathy-Kanniappan et al. (2012) Radiology 262:834-845), pancreatic cancer (Cao et al. (2008) Clin. Cancer Res. 14:1831-1839; Bhardwaj et al. (2010) Anticancer Res. 30:743-749; and Ota et al. (2013) Target Oncol. 8:145-151), brain tumor (El Sayed et al. (2012) J. Bioenerg. Biomembr. 44:61-79; Davidescu et al. (2012) J. Bioenerg. Biomembr. 44:51-60) and breast cancer (Buijs et al. (2013) J. Vasc. Interv. Radiol. 24:737-743). Together, the inhibition of GAPDH and the molecular specificity of 3-BrPA have established that targeting tumor glycolysis via 3-BrPA could be a viable strategy in treating cancer, especially solid malignancies (Ganapathy-Kanniappan et al. (2012) Oncotarget 3:940-95; Ganapathy-Kanniappan et al. (2013) Anticancer Res. 33:13-20).
Despite the potential of selective ATP inhibitors, such as 3-halopyruvates like 3-BrPA, for therapeutic use, however, there are several factors that have hampered development of systemic administration formulations. For example, the alkylation (chemical) properties of 3-halopyruvates and related compounds render them very reactive with electrophilic molecules that has generally required increases in dosing with the negative effect of increasing toxicity, especially increased alkylation near the injection site. In particular, the presence of water or any nucleophilic group, such as amino or sulfhydryl groups commonly found in proteins, chemically inactivates the compound. Also, the in vivo stability of such compounds is influenced by multiple factors including glutathione, NADH and other reducing molecules in the blood and circulatory system. Hence, it is critical that the compounds remain unaffected by such factors, at least until the first pass of circulation.
While recognizing that protecting selective ATP inhibitors, such as 3-halopyruvates like 3-BrPA, until they are delivered to organs or tissues is critical for their antitumor efficacy under systemic delivery, numerous approaches to achieve such protection, such as encapsulating them in liposomes, microspheres, nanospheres, nanoparticles, bubbles, and the like, have not been successful. For example, it is known that molecules such as 3-BrPA undesirably leach out rapidly from PEGylated liposomes or react with proteins such as albumin in albumin-based nanoparticles. Although sporadic reports have documented the intraperitoneal delivery of 3-BrPA in preclinical models, the efficacy and dosage regimen were very limited. Due to these failures, 3-BrPA therapies are currently relegated to loco-regional delivery (e.g., percutaneous ablation, intra-arterial delivery, and intra-tumoral injections) as opposed to systemic delivery (Kunjithapatham et al. (2013) BMC Res. Notes 6:277).
Accordingly, there is a great need in the art to identify compositions of selective ATP inhibitors, such as 3-halopyruvates like 3-BrPA, suitable for systemic administration.